Effect of Zinc supplementation on child development: a systematic review and metaanalysis Protocol

Child development is one of the principal aspects of pediatrics. It is a multidimensional process, on which many factors may have different effects. Zinc is a nutritional trace element that has an essential role in neuronal activity and, consequently, in brain development. Since Zinc deficiency is prevalent in developing countries, some clinical trials were conducted to evaluate the impact of zinc supplementation on child development. Thus, we decided to run a systematic review in this area to identify the effectiveness of zinc supplements on child development. This systematic review protocol will include randomized controlled trials studies (RCTs) in which zinc supplementation was used versus placebo or no intervention, zinc supplementation with other micronutrients versus the same micronutrients without zinc. We will evaluate the effect of zinc alone and zinc co-supplementation with iron on child development. We will search the Medline, Pubmed, EMBASE, ERIC, Psychinfo, the Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), ISRCTN Registry CINAHL, Web of Science and Scopus databases. The clinicaltrials.gov and the Cochrane Library website will also be searched for randomized trials which were registered and completed but not published yet. Two researchers will independently screen titles and abstracts of citations and read the full texts of potentially relevant studies. The data extraction and quality assessment of the papers will be done independently. Any disagreements that arise between the reviewers in the above-mentioned steps will be resolved through discussion. We will report our findings based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and use the Cochrane Collaboration’s tool for assessing the risk of bias. We will aim to synthesize the results in a meta-analysis if the interventions are similar in methods. Based on the similarities and differences of primary studies, we will use the best statistical methods. This is a protocol of systematic Review and meta-analysis of the effect of zinc supplementation on child development. The strengths of this protocol after meta-analysis are as follows: We will identify the strengths and weaknesses of each study. We will also study if zinc alone and zinc co-supplementation with iron are useful for improving child development in terms of their age, their nutritional status, dose of the zinc supplementation, type of the zinc supplementation (salt), duration of the intervention and iron or other nutrient co supplementations. We will assume that the measures used for the outcome will be heterogeneous between studies. We know that each study has its own quantity. We will use the random effect models for these heterogeneous data.


Introduction
Child development is one of the most important aspects of pediatrics. It ensures that children who grow up in the right direction can provide an opportunity for a healthy life. Therefore, the health promotion of children is one of the most important tasks, for which governments must be accountable. Zinc deficiency is a health problem in undeveloped or developing countries. It is a prevalent issue among the undernourished children and may result in their poor development (8). An estimated 17.3% of the world's population is at risk of inadequate zinc intake (9). The main intervention strategies for the prevention of zinc deficiency include dietary modification, supplementation, and fortification. Therefore, many health policymakers in underdeveloped regions have decided to use zinc supplementation in the primary health care services.
Some researchers evaluated the effect of zinc supplementation on child development. In some trials, zinc was prescribed for young children.
One study on Canadian infants showed that zinc supplementation improved the motor development of low birth weight (LBW) in infants (10,11). containing iron and zinc on 221 rural Bangladeshi infants. They found that zinc had a beneficial effect on infant motor development when proscribed together with iron or as MM (12). In another study on 150 term Chilean neonates of low socioeconomic status who received supplemental zinc, a beneficial effect was found on the mental development and motor quality behavior of healthy term infants (13). When the micronutrient supplementation was given to urban and rural children in china along with zinc, their range of neuropsychological function was much more improved than when they took micronutrient alone (14) . Studies conducted in Indonesia (15) and Brazil (16) did not show any effect of zinc supplements on infant development.
In another study, a zinc did not have any beneficial effect on the motor development of infants at 10 months of age (17). In a similar way, there were no relations between zinc supplementation and motor development of rural Guatemalan infants

Setting and time frame
No limitation will be considered in this systematic review for setting and time frame.

Report characteristics
In this systematic review, we selected only those articles with English abstracts and those published at the time of the search.

Information sources
We will search PubMed, MEDLINE (Ovid),

Search strategy
Our initial search syntax for MEDLINE will be: 1: zinc.tw. or babies or toddler* or boy* or girl* or child* or preschool* or pre-school* or school* or schoolchild* or preteen* or pre-teen* or preadolescen* or pre-adolescen*).tw. 9: 4 or 5 or 6 or 7 or 8

Study records Selection process
We will import all search citations into Endnote and remove the duplication. The two referees will then evaluate the citations independently according to the criteria in the titles and abstracts. They will categorize the articles into three groups as relevant, unsure, and not relevant. Those articles, classified as not related by both reviewers, will be excluded from the study. We will resolve any disagreements via consensus discussions. Then, two review authors read the full-texts of relevant surveys and extract their data independently. They will also make a list of articles to be included and code the quality of the papers, independently. Any disagreements will be resolved via consensus discussions by the research team, who will make the final decision.
Data management: For each included study, we will extract the data using an extraction sheet and record them via a piloted data collection form. We will discuss any disagreements among the extracted data to reach a consensus. When necessary, we will In this article, we will include a list of excluded studies with the reasons, and we will document all decisions.

Assessment of risk of bias in included studies
Two reviewers will separately assess the quality of included studies using the Cochrane Collaboration's risk of bias tool (25). The risk of biases in each domain (e.g., selection bias, performance bias, attrition bias, detection bias and reporting bias) will be organized as low, high, or unclear risk.

Data synthesis
PRISMA flow chart will be used to report the steps in the search strategy. To evaluate the effect of zinc alone and zinc co-supplementation with iron on child development, we will plan to synthesize results in a meta-analysis if the interventions are similar in methods and conduct subgroup metaanalyses. If the standard deviation is not reported in the reviewed articles, we will calculate the missing SDs with the existing information in the article.
Continuous data will be analyzed by computing the standardized mean difference with 95% confidence intervals (CIs). For dichotomous data, we will calculate the effect size as Odds Ratios (ORs) with their 95% CIs. Where studies have more than one intervention group (multi-arm studies), we consider groups that use zinc supplementation (as opposed to zinc supplementation) to compare a single pair and in situations where only one intervention arm is relevant to our study. Based on the similarities and differences of primary studies, we will use the best method of fixed-effect or random-effects model to assess the impact of statistical heterogeneity.
After categorizing the studies and performing the data synthesis, the final report will be prepared following the PRISMA guidelines.
If the quantitative synthesis is not appropriate, we will not perform a meta-analysis, and data will be presented descriptively.
We will use RevMan 5.3 for the risk of bias and STATA 14 for statistical analysis.

Subgroup analysis and investigation of heterogeneity
Depending on the sample size of studies and heterogeneity of study populations, we plan to undertake subgroup analyses as follows: age of the children, low birth weight children dose of the zinc supplementation, type of the zinc supplementation (salt), duration of the intervention and other nutrient co supplementations. To limit the risk of multiple comparisons, we will conduct subgroup analyses only on the primary outcomes.

Sensitivity analysis
In this review, we will conduct sensitivity analyses to determine whether or not the findings are sensitive to restricting the analyses to those studies that judged to be at low risk of bias. Additionally, we will examine if studies with high rates of inadequate blinding or loss to follow-up are more likely to show positive outcomes. We will also undertake the sensitivity analyses to assess the potential impact of missing outcome data. The results of sensitivity analyses will be reported in a summary table.

Assessment of heterogeneity
We will assess the statistical heterogeneity by inspecting the forest plots, calculating I 2 statistic with 95% CIs and employing a Chi 2 test of heterogeneity to determine the strength of evidence that heterogeneity is actual.

Metabias
In this systematic review, funnel plots will be used to assess publication bias. We will follow the recommendations on testing for funnel plot asymmetry as it is described in the Cochrane Handbook for Systematic Reviews for Interventions (25).

Confidence in cumulative evidence
The Grades of Recommendation and Assessment and Development and Evaluation (GRADE) approach will be used to assess the quality of evidence (26).

In Conclusion
In this study, we will identify each study's strengths and weaknesses. We hope to find the most useful zinc supplementation methods to translate them into clinical practices. We will disseminate this protocol in a related peer-reviewed journal.